We isolated a peripheral membrane protein interactive with lymphocytic choriomeningitis virus (LCMV) from cells permissive to LCMV infection. Examination of tryptic peptides revealed its identity as alpha-dystroglycan (alpha-DG). Four strains of LCMV, ARM 53b, Traub, E-350, WE54 and ARM C1 13 and other arenaviruses, Lassa fever virus (LFV), Oliveros, Mobala and Mopeia bound to purified alpha-DG protein. Several lines of evidence indicated that alpha-DG is required for virus infection: 1) soluble alpha- DG blocked either LCMV or LFV infection; 2) cells bearing a null mutation of the DG gene were resistant to LCMV infection; 3) reconstitution of DG expression in null mutant cells restored susceptibility to LCMV infection. Some viruses bound at high affinity to alpha-DG (C1 13, Traub, WE54, LFV) while others (ARM 53b, E-350) bound at lower affinity (100- to 1000-fold less). The high affinity alpha-DG binders, when injected into mice, preferentially infected cells in the splenic white pulp (preliminary identified as interdigitating dendritic cells (IDDC), the major antigen presenting cell), caused immunosuppression and a persistent infection. In contrast, low alpha-DG binders preferentially bound to cells in the red pulp (primarily F4/80+ cells), there was no suppression of immune response, CD8+ T cells were generated and infection terminated. We propose three specific aims. First, to determine whether alpha-DG is a common cellular receptor for all arenaviruses. Study of BSL-4 and BSL-3 arenaviruses will be done in the BSL-4 facilities at CDC and BSL-2 arenaviruses at TSRI. Second, we will make a series of alpha-DG deletion mutants and reconstitute these into DG null cells to map out the portion on alpha-DG that arenaviruses bind to to determine different or similar sites on alpha-DG that these viruses recognize. Third, we will test the hypothesis that binding to IDDC is dependent on specific aa(s) in the viral GPI (aa 260 aliphatic: high affinity binder; aromatic: low affinity). We will also analyze alpha-DG content on IDDC and F4/80+ cells and look for coreceptor(s).